title: The casein kinase 2-nrf1 axis controls the clearance of ubiquitinated proteins by regulating proteasome gene expression.
abstract: Impairment of the ubiquitin-proteasome system (UPS) has been implicated in the pathogenesis of human diseases, including neurodegenerative disorders. Thus, stimulating proteasome activity is a promising strategy to ameliorate these age-related diseases. Here we show that the protein kinase casein kinase 2 (CK2) regulates the transcriptional activity of Nrf1 to control the expression of the proteasome genes and thus the clearance of ubiquitinated proteins. We identify CK2 as an Nrf1-binding protein and find that the knockdown of CK2 enhances the Nrf1-dependent expression of the proteasome subunit genes. Real-time monitoring of proteasome activity reveals that CK2 knockdown alleviates the accumulation of ubiquitinated proteins upon proteasome inhibition. Furthermore, we identify Ser 497 of Nrf1 as the CK2 phosphorylation site and demonstrate that its alanine substitution (S497A) augments the transcriptional activity of Nrf1 and mitigates proteasome dysfunction and the formation of p62-positive juxtanuclear inclusion bodies upon proteasome inhibition. These results indicate that the CK2-mediated phosphorylation of Nrf1 suppresses the proteasome gene expression and activity and thus suggest that the CK2-Nrf1 axis is a potential therapeutic target for diseases associated with UPS impairment.
authors.affiliation: Laboratory for Genetic Code, Graduate School of Life and Medical Sciences, Doshisha University, Kyotanabe, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tsuchiya
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taniguchi
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Ito
authors.forename: Tomoko
authors.initials: T
authors.lastname: Morita
authors.forename: M Rezaul
authors.initials: MR
authors.lastname: Karim
authors.forename: Norihito
authors.initials: N
authors.lastname: Ohtake
authors.forename: Kousuke
authors.initials: K
authors.lastname: Fukagai
authors.forename: Takao
authors.initials: T
authors.lastname: Ito
authors.forename: Shota
authors.initials: S
authors.lastname: Okamuro
authors.forename: Shun-Ichiro
authors.initials: S
authors.lastname: Iemura
authors.forename: Tohru
authors.initials: T
authors.lastname: Natsume
authors.forename: Eisuke
authors.initials: E
authors.lastname: Nishida
authors.forename: Akira
authors.initials: A
authors.lastname: Kobayashi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D047390:Casein Kinase II / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D015533:Transcriptional Activation; D057149:Ubiquitinated Proteins / Q000378:metabolism*
chemical_list: D051266:Nuclear Respiratory Factor 1; D057149:Ubiquitinated Proteins; D047390:Casein Kinase II; D046988:Proteasome Endopeptidase Complex